Communication deficits accompany a wide array of developmental disorders and adult-acquired neurological diseases. The neurobehavioral genetic bases for these deficits are poorly understood, rendering treatment challenging yet motivating experimental investigation. Songbirds are advantageous models for uncovering the neural basis for human vocal communication given their structural and functional similarities to humans and the ability to conduct molecular, physiological, and behavioral manipulations not feasible in humans. This proposal focuses on dopaminergic (DA) regulation of a key candidate molecule, Synaptotagmin 4 (Syt4), in basal ganglia circuitry dedicated to learned vocalizations using the songbird model. In both songbird and human basal ganglia, DA regulates pathways important for behavior; when dopamine is lost as occurs in Parkinson's Disease (PD), vocal and non-vocal motor symptoms arise. The molecular pathways that mediate the vocal changes, currently unknown, must be determined in order to remediate this facet of the disease. Recent converging evidence highlights the importance of Syt4 in these pathways. Our studies on Syt4 gene expression show that its levels within the song-dedicated sub-region of the songbird basal ganglia are tightly linked to singing. Bioinformatic studies from the lab predict that Syt4 interacs with other genes in a DA pathway supporting learned vocal behavior. Additional findings implicate Syt4 in human cognitive specializations that distinguish our species from other primates. I thus hypothesize that dopaminergic regulation of Syt4 is functionally specific to vocal pathways, and that loss of DA converts Syt4 regulation from being driven by patterned activity associated with vocalizing to generalized non-specific activity. To test this, I will first determie whether Syt4 is regulated by natural fluctuations in DA that occur during vocal behavior under different social contexts and in a Parkinsonian-like state. Follow up experiments will then test whether loss of DA, such as occurs in PD, switches Syt 4 regulation to that found in non-vocal areas. Results from these aims will provide insight into molecular mechanisms operating in the basal ganglia to support vocal behavior in songbirds and potentially, humans, with the promise of new therapeutic targets to treat vocal disorders. PUBLIC HEALTH RELEVANCE: Communication deficits are a debilitating component in a wide range of developmental disorders (e.g. Autism Spectrum) and adult-acquired neurological diseases (e.g. Parkinson's) with additional negative effects on mental health. The neural and genetic bases for speech deficits are not well-understood. My proposal uses an advantageous animal model for speech, the vocal-learning songbird, to test whether a gene that is linked to birdsong, Synaptotagmin 4, is important in brain pathways for normal vocalization and whether it becomes misregulated in a Parkinsonian-like state.